To help meet the Challenge Goal of eliminating suffering and death from cancer by 2015, the NCI must capitalize on the extraordinary momentum generated by advances in human genetic research. The sequencing of the human genome and the annotation of common variations, together with new technologies for analyzing single nucleotide polymorphisms (SNPs), have provided the tools for investigators to actively search for inherited variants in genes that can increase or modify cancer risk. The C-GEMS proposal will use the latest genomic technologies to perform dense whole genome scans to identify and validate susceptibility genes in the induction and progression of breast and prostate cancer, and clarify gene-gene and gene-environment interactions. This work will provide new insights into mechanisms of carcinogenesis, and point the way to novel strategies for meeting the 2015 Challenge Goal by accelerating the prevention, early detection, and treatment of cancer.Prostate cancer, lung cancer, bladder cancer, breast cancer, colorectal cancer, kidney cancer, non-Hodgkin's lymphoma (NHL), ovarian cancer, brain tumors, and endometrial cancer are the main focus of current and planned replication studies.